Ivan M. Roitt Professor Roitt was born in 1927 and educated at King Edward's School, Birmingham and Balliol College, Oxford. In 1956, together with Deborah Doniach and Peter Campbell, he made the classic discovery of thy~oglobulin autoantibodies in Hashimoto's thvroiditis J which helped to open the whole concept of a relationship between autoimmunity and human disease. The work was extended to an intensive study of autoimmune phenomena in pernicious anaemia and primary biliary cirrhosis. In 1983 he was elected a Fellow of The Royal Society, and has been elected to Honorary Membership of the Royal College of Physicians and appointed Honorary Fellow of The Royal Society of Medicine. Peter J. Delves Dr Delves obtained his PhD from the University of London in 1986 and is currently a Reader in Immunology at University College London. His research focuses on molecular aspects of antigen recognition. He has authored and edited a number of immunology books, and teaches the subject at a broad range of levels. Essential Immunology lvan M. Roitt MA, DSc(Oxon),F RDPath, Hon FRCP(Lond), FRS Emeritus Professor, Department of Immunology and Molecular Pathology, University College London, London WIT 4JF Peter J. Delves PhD Department of Immunology and Molecular Pathology, University College London, London WlT4JF Blackwell Science O 197 1, 1974, 1977, 1980, 1984, 1988, 1991, 1994, 1997,2001 by Blackwell Science Ltd a Blackwell Publishing company Blackwell Science, Inc., 350 Main Street, Malden, Massachusetts 02148-5018, USA Blackwell Science Ltd, 9600 Garsington Road, Oxford OX4 2DQ, UK Blackwell Science Asia Pty Ltd, 550 Swanston Street, Carlton, Victoria 3053, Australia The right of the Authors to be identified as the Authors of this Work has been asserted in accordance with the Copyright, Designs and Patents Act 1988. All right reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher. First published 1971 Portuguese editions 1973, 1979, 1983 Reprinted 1972 (twice), 1973 (twice) French editions 1975, 1979, 1990 Second edition 1974, Reprinted 1975 Dutch editions 1975, 1978, 1982 Third edition 1977, Reprinted 1978, 1979 Japanese editions 1976, 1978, 1982, 1986, 1988 Fourth edition 1980, Reprinted 1982, 1983 German editions 1977, 1984, 1988, 1993 Fifth edition 1984 Polish edition 1977 Sixth eidtion 1988, Reprinted 1988, 1989 Greek editions 1978, 1989, 1992 Seventh eidtion 1991 Turkish edition 1979 Eighth edition 1994, Reprinted 1996 Solvak edition 1981 Ninth edition 1997, Reprinted 1999 Indonesian editions 1985, 1991 Tenth edition 2001, Reprinted 2003,2004 Russian edition 1988 Korean edition 1991 Spanish editions 1972, 1975, 1978, 1982, 1988, 1989, 1993 ELBS editions 1977, 1982, 1988, Reprinted 1991 Italian editions 1973, 1975, 1979, 1986, 1988, 1990, 1993, Chinese (Taiwan) editions 1991 , 1994 1995 Library of Congress Cataloging-in-Publication Data Roitt, Ivan M. (Ivan Maurice) Roitt's essential immunology/Ivan M. Roitt, Peter J. Delves. - 10th ed. p.; cm. Includes bibliographical references and index. ISBN 0-632-05902-8Cpbk.) 1. Immunology. I. Title: Essential immunology. 11. Delves, Peter J. 111. Title. [DNLM: 1. Immune System. 2. Immunity. QW 504 R719e 20011 QRl8l .R57 2001 616.07'9-4~21 ISBN 0-632-05902-8 A catalogue record for this title is available from the British Library Set by SNP Best-set Typesetter Ltd., Hong Kong Printed and bound by Replika Press Pvt. Ltd., India. For further information on Blackwell Publishing, visit our website: http://www.blackwellpublishing.com Acknowledgements, vi 1 1 Control mechanisms, 200 Preface, vii 12 Ontogeny and phylogeny, 22 1 Abbreviations, viii 13 Adversarial strategies during infection, 249 Uses Guide, xi 1 4 Prophylaxis, 28 1 Innate immunity, 1 15 Immunodeficiency, 305 Specific acquired immunity, 2 1 16 Hypersensitivity, 322 Anti bodies, 37 17 Transplantation, 349 Membrane receptors for antigen, 59 18 Tumor immunology, 374 The primary interaction with antigen, 80 1 9 Autoimmune diseases l -Scope and etiology, 396 lmmunochemical techniques, 108 20 Autoimmune diseases 2-Pathogenesis, Cellular techniques, 129 diagnosis and treatment, 42 1 The anatomy of the immune response, 14 7 Appendix l :C D markers, 45 1 Lymphocyte activation, 164 Appendix 2: Glossary, 463 The production of effectors, 177 Index, 473 vi The input of the editorial team of Nick Morgan, Meg 16.10; J. Horton for figure 12.20; G. Rook for figures Barton and Fiona Goodgame at Blackwell Science, the 13.5 and 13.12; and J. Taverne for figure 13.21 and illustrator Graeme Chambers and the indefatigable table 13.1. secretarial assistance of Christine Griffin is warmly Every effort has been made by the authors and the acknowledged. Wise counsel was provided by Kirsten publisher to contact all the copyright holders to obtain Fischer Lindahl, Jurg Tschopp and Helen Turner their permission to reproduce copyright material. concerning aspects of MHC gene organization, ap- However, if any have been inadvertently overlooked, optosis and IgE receptor signaling respectively. We the publisher will be pleased to make the necessary are much indebted to the co-editors of Immunology, arrangements at the first opportunity. J. Brostoff and D. Male, together with the publishers, A number of scientists very generously provided Harcourt Health Sciences, and the following indi- illustrations for inclusion in this edition, and we have viduals for permission to utilize or modify their acknowledged our gratitude to them in the relevant figures: J. Brostoff and A. Hall for figures 1.15 and figure legends. vii It is now 30 years since the 1st Edition of Essential viral hijacking of host processes as evasion Immunology appeared, and it seemed that the time was mechanisms now appropriate for the task of producing the 10th DNA vaccines Edition to be shared. The new co-author, Peter Delves, mucosal adjuvants has been a close colleague of Professor Roitt for many 'shot gun' approach to identification of vaccine years and is a highly experienced teacher. candidates A wide range of subjects have been extensively primary immunodeficiency including IL-7 receptor revised, restructured or updated, and advanced mutation, and deficiency of VDJ recombination in material is included in the figure legends to avoid severe combined immunodeficiency disruption of the basic text. These subjects include: CCR5 CO-receptofro r HIV infection of cells dendritic cells the importance of highly active anti-retroviral drug intraepithelial lymphocytes therapy and of healthy CD8 response dependent on NK-T and y6 T-cells robust CD4 Thl effectors in control of HIV infection NK receptors pivotal role of IgE antibodies in pathogenesis receptor editing relating to receptor diversity of asthma and atopic dermatitis, and remarkable non-classical MHC and the presentation of non- therapeutic benefit of monoclonal anti-IgE peptidic antigens the excessive hygiene hypothesis related to the the role of chaperone proteins in antigen processing development of allergy T-cell recognition of peptide-MHC reflecting the the role of Fcy receptors in the pathogenesis of type latest crystallographic studies I1 and I11 hypersensitivities arrays for analysis of gene expression suppression of graft rejection by synergy between tetramer evaluation of antigen-specificT -cells fungal metabolites and other drugs and by induc- experimental genetic manipulation using con- tion of antigen-specific tolerance with high-dose ditional 'knockouts' employing the Lox/Cre bone marrow transplantation combined with system and 'knockins' to replace endogenous CO-stimulatory blockade by anti-CD40L and genes CTLA-4-Ig B- and T-cell signaling pathways and the role of engineering grafts from recipient cells adaptor proteins the role of hsp70 and 90 in natural and induced cytokine physiology tumor immunity chemokines and their receptors peptide priming of dendritic cells to provoke anti- memory cells cancer cytotoxic responses intimate links of innate and adaptive immunity the avoidance of graft vs. host disease in allogeneic the role of complement in modulating the adaptive bone marrow transplantation for leukemias immune response inhibition of B-cell lymphomas and tumor angio- regulatory T-cells genesis by radiolabeled monoclonals activation-induced cell death thymic expression of some organ-specific antigens neuroendocrine influences on the immune system role of autoimmunity to hsp65 in atherosclerosis critical role of Pax 5 in B-cell differentiation autologous stem cell transplantation after cytotoxic molecular basis of thymic development ablative therapy for some cases of SLE, scleroderma signaling through pattern recognition systems and juvenile rheumatoid arthritis. prions All in all, quite a mouthful! viii Ab antibody DAG diacylglycerol ACh-R acetylcholine receptor DC dendritic cells ACTH adrenocorticotropic hormone DNP dinit rophenyl ADA adenosine deaminase DTP diphtheria, tetanus, pertussis triple vaccine ADCC antibody-dependentc ellular cytotoxicity EAE experimental allergic encephalomyelitis Ag antigen EBV Epstein-Barr virus AIDS acquired immunodeficiencys yndrome ELISA enzyme-linked immunosorbent assay ANCA antineutrophil cytoplasmic antibodies EM electron microscope APC antigen-presentingc ell E@ eosinophil ARRE-1 antigen receptor response element-l ER endoplasmicr eticulum ARRE-2 antigen receptor response element-2 ES embryonic stem (cell) AZT zidovudine (3'-azido-3'-deoxythymidine) F(B) factor (B, etc.) B-cell lymphocyte which matures in bone marrow Fab monovalent Ig antigen-bindingf ragment after BCG bacille Calmette-GuQin attenuated form of papain digestion tuberculosis divalent antigen-bindingf ragment after pepsin BCR B-cell receptor digestion BM bone marrow FACS fluorescence-activatedc ell sorter BS A bovine serum albumin Fc Ig crystallisable-fragment originally; now non-Fab BUDR bromodeoxyuridine part of Ig C complement Fc yR receptor for IgG Fc fragment C~(P/Y/~) constant part of TCR a(P/y/6) chain FDC follicular dendritic cells CALLA common acute lymphoblastic leukemia antigen (sc)Fv (single chain) VH-VLa ntigen binding fragment CAMP cyclic adenosine monophosphate G granulocyte CCP complement control protein repeat g.b.m. glomerularb asement membrane CD cluster of differentiation GM-CSF granulocyte-macrophage colony-stimulating CDR complementarity determining regions of Ig or TCR factor variable portion gPn nkDa glycoprotein CEA carcinoembryonica ntigen g.v.h. graft versus host CFA complete Freund's adjuvant H-2 the mouse major histocompatibility complex cGMP cyclic guanosine monophosphate H-2D/K/L main loci for classical class I (class 11) constant part of Ig heavy (light)c hain (Am murine MHC molecules cell-mediated immunity HAMA human antimouse antibodies CML cell-mediated lympholysis HBsAg hepatitis B surface antigen CMV cytomegalovirus hCG human chorionic gonadotropin Cn complement component 'n' HEV high walled endothelium of post capillary cii activated complement component 'n' venule iCn inactivated complement component 'n' Hi high Cna small peptide derived by proteolytic activation of HIV- 1( 2) human immunodeficiency virus-l (2) Cn HLA the human major histocompatibility complex CPG guanosine-cytosine HLA-A / B/ C main loci for classical class I (class 11) CR(n) complement receptor 'n' (DP/ DQ / DR) human MHC molecules CRP C-reactivep rotein HRF homologous restriction factor CsA cyclosporin A HSA heat-stable antigen CSF cerebrospinal fluid hsp heat-shock protein D gene diversity minigene joining V and J segmentst o 5HT 5-hydroxytryptamine form variable region HTLV human T-cell leukemia virus DAF decay accelerating factor H-Y male transplantation antigen ICAM-1 intercellular adhesion molecule-l NADP nicotinamide adenine dinucleotide phosphate Id (aId) idiotype (anti-idiotype) NAP neutrophil activating peptide IDC interdigitating dendritic cells NBT nitro blue tetrazolium IDDM insulin-dependent diabetes mellitus NCF neutrophil chemotacticf actor IFNa a-interferon (also IFNP, IFNy) NFAT nuclear factor of activated T-cells Ig immunoglobulin NFKB nuclear transcription factor IgG immunoglobulin G (also IgM, IgA, IgD, IgE) NK natural killer cell SI g surface immunoglobulin NO. nitric oxide IgM-a&-P membrane peptide chains associated with sIgM B- NOD Nonobese diabetic mouse cell receptor NZB New Zealand Black mouse IgS F immunoglobulin superfamily NZB X W New Zealand Black mouse X NZ White F1 hybrid IL-1 interleukin-l (also IL-2, IL-3, etc.) .o, superoxide anion iNOS inducible nitric oxide synthase OD optical density IP3 inositol triphosphate ORF open reading frame ISCOM immunostimulating complex OS obese strain chicken ITAM immunoreceptor tyrosine-based activation motif Ova ovalbumin ITIM immunoreceptor tyrosine-based inhibitory PAF(-R) platelet activating factor (-receptor) motif PCA passive cutaneous anaphylaxis idiopathic thrombocytopenic purpura PCR polymerase chain reaction Janus kinases PG(E) prostaglandin (E etc.) peptide chain in IgA dimer and IgM PHA phytohemagglutinin joining gene linking V or D segment to constant phox phagocyte oxidase region PIP, phosphatidylinositol diphosphate association (dissociation)a ffinity constant (usually PKC protein kinase C Ag-Ab reactions) PLC phospholipase C kDa units of molecular mass in kilo Daltons PMN polymorphonuclear neutrophil KLH keyhole limpet hemocyanin PMT photomultiplier tube LAK lymphocyte activated killer cell PNH paroxysmal nocturnal hemoglobinuria LATS long-acting thyroid stimulator PPD purified protein derivative from Mycobacterium LBP LPS binding protein tuberculosis LCM lymphocytic choriomeningitis virus PTK protein tyrosine kinase Lea/b/x ~ewis~b/l~oo/d" g roup antigens PWM pokeweed mitogen LFA-1 lymphocyte functional antigen-l RA rheumatoid arthritis LGL large granular lymphocyte RANTES regulated upon activation normal T-cell expressed LHRH luteinizing hormone releasing hormone and secreted chemokine LIF leukemia inhibiting factor RAST radioallergosorbent test L0 low RF rheumatoid factor LT(B) leukotriene (B etc.) RW) rhesus blood group (D) LPS lipopolysaccharide (endotoxin) R01 reactive oxygen intermediates M@ macrophage SAP serum amyloid P mAb monoclonal antibody SC Ig secretory component MAC membrane attack complex SCF stem cell factor MAdCAM mucosal addressin cell adhesion molecule scFv single chain variable region antibody fragment MALT mucosal-associatedl ymphoid tissue (V, +V, joined by a flexible linker) MAP kinase mitogen-activated protein kinase SCG sodium cromoglycate MBP basic protein of eosinophils (also myelin basic SCID severe combined immunodeficiency protein) SDS-PAGE sodium dodecylsulfate-polyacrylamide gel MC mast cell electrophoresis MCP membrane cofactor protein (C' regulation) SEA(Be tc.) Staphylococcus aureus enterotoxin A (B etc.) MCP-1 monocyte chemotacticp rotein-l SIV Simian immunodeficiencyv irus M-CSF macrophage colony-stimulating factor SLE systemic lupus erythematosus MDP muramyl dipeptide SRID single radial immunodiffusion MHC major histocompatibility complex STAT signal transducer and activator of transcription MIF macrophage migration inhibitory factor TAP transporter for antigen processing MLA monophosphoryl lipid A T-ALL T-acute lymphoblastic leukemia MLR mixed lymphocyte reaction TB tubercle bacillus MMTV mouse mammary tumor virus Tc cytotoxic T-cell MS multiple sclerosis T-cell thymus-derived lymphocyte MSH melanocyte stimulating hormone TCRl(2) T-cell receptor with y/6 chains (with a/ MuLV murine leukemia virus p chains)